Novel FSHR variants causing female resistant ovary syndrome

Pathogenic variants of follicle-stimulating hormone receptor (FSHR) are known to cause amenorrhea and infertility in women. However, only a limited number of pathogenic FSHR variants have been reported, and few reports described detailed characteristics of patients with pathogenic FSHR variants.

The affected siblings and both parents were subjected to whole-genome exon sequencing. Transient transfection of HEK 293T cells was performed with constructed vectors. The cellular localization of the FSHR protein was evaluated using confocal microscopy, and cyclic adenosine monophosphate (cAMP) production was detected with a cAMP ELISA kit.

A Chinese family with two siblings carrying compound heterozygous pathogenic variants of FSHR: c.182T>A (p.Ile61Asn) and c.2062C>A (p.Pro688Thr). Both siblings had amenorrhea, infertility, and resistance to gonadotropin (Gn) stimulation but showed high anti-Müllerian hormone levels and early antral follicles. Molecular dynamics simulations of the FSHR variants revealed significant changes in structural characteristics and electrostatic potential. In vitro analysis indicated that the p.Ile61Asn variant lacked cell surface localization and completely abolished the cAMP second messenger response. The p.Pro688Thr variant retained cell surface localization but caused decreased FSH-induced cAMP production.

We found two novel pathogenic FSHR variants causing resistant ovarian syndrome. This study expands the genotypic spectrum of pathogenic FSHR variants and our knowledge of phenotype-genotype correlations.